Bioactive Marine Peptides 31 Marine Algae

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Certain varieties of Lyngbya majuscula,19-27 a toxic marine blue-green alga found in warm water have been implicated as the causative agents of Swimmer's'itch, a form of contact dermatitis. Lyngbyatoxin-A ( 1)28-5 was isolated from L. majuscula and the gross structure was determined as the prenylated cyclic dipeptide. The configuration at the C-14 quaternary carbon in (1) was subsequently shown to be (R) by degradation of (1) to dimethyl 2(S)-2-ethyl-2-methylglutarate.36 Lyngbyatoxin-A (1) represents a new structural class of potent tumor promoters that exhibits tumor promoting activity in mice similar to that induced by phorbol esters.37 Lyngbyatoxin-A was also found to kill baitfish (Poecilia vittata) at a concentration of 0.15 ^g/ mL in seawater suggesting L. majuscula perhaps produce lyngbyatoxin-A as an ichthyotoxic chemical for defense. Lyngbyatoxin-A has been synthesized.38

Blue-green alga Microcystis aeruginosa has yielded four new protease inhibitors, micropeptins SD944 (2), SD979 (3), SD999 and SD1002.39'40 Micropeptins SD944 (2) and SD999 inhibited trypsin with IC50 at 8.0 and 4.0 ^g mL- , respectively, but both compounds did not inhibit chymotrypsin at 45 ^g mL1 . Micropeptin SD979 and SD1002 inhibited chymotrypsin at 2.4 and 3.2 ^g mL- , respectively, but not trypsin at 18.0 ^g mL1 . The structures of these peptides were elucidated on the basis of 2D NMR data and chemical degradation. Microginin (4)41 has been isolated from M. aeruginosa and it inhibited angiotensin converting enzyme (IC50, 7.0 ^g/mL), but did not inhibit pepsin, trypsin, chymotrypsin and elastase at 100 ^g/mL. A Venezuelan sample of the blue-green alga Lyngbya majuscula had recently furnished two new immunosuppressive peptides microcolin-A (5) and microcolin-B (6).42-5 The microcolins are potent inhibitors of the murine mixed lymphocyte response and murine P-388 leukemia in vitro.

3.2 Sponges

Marine sponges continue to be source of secondary metabolites with unusual chemical diversity and remarkable biological activity. Large number of peptides have been isolated from marine sponges. They have attracted considerable attention because of their unique structural framework, rich physiochemical properties, and thus potential as important drug candidates.4649 The sponges so far had furnished only a few ftue"peptides. Most sponge peptides are highly modified whereas some contains unusual amino acids. Sponges provide lodging to many organisms, such as brittle stars, bivalve, gastropods, crustaceans, and annelid worms. Sponge peptides are suspected to be of microbial origin because some of them contain D-amino acids and unusual amino acids. Fusetani et al50 were the first to isolate bioactive peptide discodermin A from the marine sponge Discodermia kiiensis in 1985. The peptide contained the rare tert leucine, cysteic acid and several D-amino acids. Since this report many peptides had been isolated from marine sponges, some of which not only exhibit interesting biological activities but also contain new amino acids.14 Several reasons have been given for the rapid progress in the chemistry of sponge peptides; development of reversed-phase HPLC enabled the isolation of peptides from a mixture of related metabolites. Advances in spectroscopy, especially 2D NMR and FAB mass spectrometry for structural determination because sequence analysis of unusual peptides cannot be accomplished by Edman degradation due to the presence of blocked N-termini and/or amino acid residues. Progress in chiral chromatography allowed the assignment of absolute configuration of amino acids with small amount of material. Lastly, the marine natural product chemists happen to investigate sponges of the order Lithistida, rich in bioactive peptides. Sponge peptides have been reviewed.14,16,46 The species that have yielded bioactive peptides are: Jaspis, Pseudaxinyssa, Geodia, Discodermia, Theonella, Cliona, Axinella, Pseudoaxinella, Malaysistin, Leucophloeus and Hymeniacidon.

Jaspamide (7)51-7 was the first bioactive peptide isolated from a sponge of the genus Jaspis from Fiji and Palan. MeOH extract of Jaspis was obtained by soaking 73 g of pulverized freeze-dried tissue. The methanol extract was subjected to a solvent partition to give 500 mg material which was found solubale in CCl4 and CHCl3. Filtration of this material through a silica gel 60 column (2.4 cm x 10 cm, EtOAc) followed by HPLC (Partisil 10, 4.6 mm x 25 cm; EtOAc/Hexane, 8:2) gave jaspamide (7) as a colorless oil. Molecular formula of (7) was established as C36H45BrN4O6 by HR-FABMS C36H45BrN4O6 (MH+ 709.2596). The depsipeptide nature of jaspamide was evident from IR bands at 1715, 1684, 1674 and 1638 cm1 and 13C NMR signals at 8 175.1, 174.4, 170.5, and 168.9 ppm indicating the presence of four carbonyl functionality. Finally, the structure (7) was confirmed by extensive 2D NMR spectroscopic data.

Total synthesis ofjaspamide (7) has been accomplished. Jaspamide exhibited insecticidal activity against Heliothis verescens with an LC50 of 4 ppm. It was toxic to nematode [Nippostrongylus brasiliensis (LD50 < 1 ^g/mL)]. Jaspamide showed in vivo topical activity against a vaginal Candida infection in mice and was cytotoxic against a larynx epithelial carcinoma cell line (IC50 0.32 ^g/mL) and a human embryonic lung cell line (IC100 0.01 ^g/mL).

Sponges of the genera Discodermia and Theonella had proved to be a rich source of bioactive peptides. Discodermins were the first bioactive peptides isolated from marine sponge.58,59 Discodermins A-D (8-11) were isolated from D. kiiensis. They are tetradecapeptides with the N- terminus blocked by

7
Bioactive Peptides And Origin

a formyl group and the C-terminus lactonized with the ninth (Thr.) residue from the N-terminus.

The structure of discodermins B-D (9-11) differed in the fourth and fifth amino acid residues, which were Val-t-Leu in discodermin B, t-Leu-Val in discodermin C, and Val-Val in discodermin D. The most unusual component in the discodermins is the t-Leu residue, which had only been reported as a constituent of actinomycete peptides, bottromycins.60-3 These facts along with the presence of several D-amino acids suggest the microbial origin of discodermins. Discodermin A inhibited Bacillus subtilis and Proteus mirabilis at 3 and 1.6 jg/mL concentrations respectively. Discodermins also inhibited the development of starfish embryos at concentrations 2-20 jg/mL. They were found to be potent inhibitors against phospholipase A2 (IC50, 3.5-7.0 x 10- M).64 Discodermin A exhibited antiinflammatory activity in the mouse ear pretreated with okadaic acid. Discodermin A also inhibited tumor promotion by okadaic acid. Treatment with 500 jg of discodermin A before application of okadaic acid (1 jg) reduced the percentage of tumor bearing mice from 86.7% to 46.7% and the average number of tumors per mouse from 4.7 to 1.1.14

Caribbean sponge Discodermin sp. collected at a depth of 274 m off the coast of St. Lucia, Lesser Antilles furnished a bioactive peptide, polydiscamide A65 which had common structural features as discodermins. Polydiscamide A was cytotoxic against the cultured human lung cancer A549 cell line with an IC50 of 0.7 jig/mL and inhibited B. subtilis with an MIC of 3 jg/mL. Discodermia kiiensis had yielded unrelated cyclic depsipeptides, namely discokiolide A-C (12-14).66 These peptides had unusual P-hydroxy acids as well as P-methoxyphenylalanine residues. The mixture of peptides was separated by reversed-phase HPLC after conversion to the methyl esters.

B16 Cell Ic50

Discokiolides exhibited marginal cytotoxic activity; IC50 ^g/mL. P388, 2.6, P388/ADM, 7.2, B16-BL6; 1.6, Lewis, 1.2; Lu-99, 0.7; HT-29, 1:2; CCD-19Lu 0.5. Eight bioactive peptides calyculins A-H containing an octamethyl polyhydroxylated C28 fatty acid linked to two amino acids were isolated from the sponge Discodermia calyx.67,68 Absolute stereochemistry of the calyculins was determined on the basis of CD spectrum of an amino acid fragment obtained by acid hydrolysis,69 which was later confirmed by a synthesis of the fragment70 and total synthesis of an enantiomer of calyculin A.71 Calyculin A (15) exhibited in vivo antitumor, cytotoxic and antifungal activities. Calyculin A showed potent tumor promoter activity.72 It inhibited protein phosphatases 1A and 2A.73 An Okinawan Theonella sp. had yielded cyclic peptides, named keramamides B-D (16-18).74 Another related peptide keramamide F (19) was also obtained from the same sponge.75 Keramamide F (19) was found moderately cytotoxic, whereas keramamides B-D (16-18) inhibited the generation of super oxide anion in human neutrophils treated with formyl-Met-Leu-Phe at concentrations of 5 x 10- M.

Konbamide (20)76 and keramamide-A (21),77 were isolated from Okinawan Theonella sponge and found to be moderate inhibitors of calmodulin-activated phosphodiesterase and Ca2+-ATPase, respectively. Both the peptides had common pentapeptide feature, the side-chain amino group in the N-terminal Lys residue formed an amide bond with the C-terminal carboxyl group and the amino group of the Lys residue formed as urea bond with an amino acid. Hymenamide7880 A and B (22, 23) the two cyclic heptapeptides having a prolylproline segment have been isolated from the Okinawan marine sponge Hymeniacidon sp. Their structures have been elucidated on the basis of 2D NMR and FAB-MS data.

19

Hymenamides A, B (22,23, respectively) showed antifungal activity against Candida albicans (MIC 33 and 66 ^g/mL respectively) and Cryptococcus neoformans (<133 and 33 ^g/mL, respectively). Hemanamide B (23) also showed cytotoxicity against murine lymphoma-L 1210 cells and human epidermoid carcinoma KB cells with IC50 value of 3.2 and 6.0 p,g/ml in vitro, respectively.

Theonella sp. have been a source of structurally diverse biologically active peptides.46 Recently, phakellistatins (phakellistatins 1-11 and isophakellistatin

13), a series of cyclicpeptides, have been isolated from Phakellia sp. (class Demospongiae, order Axinellida).81-89 All of the phakellistatins have common proline unit. Phakellistatins exhibit moderate cytotoxicity.81 Phakellistatin 1 (24),81 a cell growth inhibitory (P-388 murine leukemia, (ED50 7.5 ^g/mL) cycloheptapeptide was isolated from two Indo Pacific sponges, Phakellia costata and Stylotella aurantium. Its structure was accomplished using high field NMR, amino acid analyses and mass spectral techniques (FAB, Tandem MS) followed by chiral gas chromatographic procedures for absolute configuration assignments (all S-amino acid units). The structure (24) was finally confirmed by X-ray analysis.

The ascidians Lissoclium patella collected from Pulan Salu, Singapore yielded a cyclic peptide patellamide E (25)90 which exhibited mild cytotoxicity against human colon tumor cells in vitro (IC50 125 ^g/mL). Nazumamide-A (26),91 a thrombin inhibitory linear tetra peptide of marine origin, was efficiently constructed using diethyl phosphorocyanidate (DEPC) as coupling reagent and tert-butyloxycarbonyl as the temporary N-protecting group. The protecting groups were finally removed by catalytic hydrogenation.

Ethanol extraction of the frozen sponge Discodermia sp. collected from Bahamas at a depth of 180 m, yielded an extract which was partitioned between EtOAc and H2O. The EtOAc soluble fraction on bioassay guided silica-gel chromatography followed by reversed-phase HPLC purification furnished two antifungal peptidesdiscobahamin-A ( 27) and discobahamin-

Discobahamins are related structurally to cyclic peptides orbiculamide A92 and keramamides B-D isolated from Theonella sp.93 Both discobahamin A and B exhibited weak antifungal activity against the yeast form of Candida

24
o

28, R = Me albicans. A sponge of the genus Theonella collected at a depth of 15 m by SCUBAnear Perth, Western Australia contained a cyclic octapeptide perthamide B,94 Its structure was elucidated by spectroscopic methods.

Perthamide B (29) weakly inhibited the binding of [125I] IL-1 to intact EL 4.6.1 cells with IC50 27.6 |M. Methanolic extract of the frozen sponge was partitioned between n-butanol and water. The residue of the active organic layer was chromatographed on an LH-20 stationary phase and further purified by HPLC to give perthamide-B, m.p. 228-231 °C.

Give Organism

Most of the bioactive peptides isolated from marine sponges are cyclic and lipophilic. The chemists involved in the isolation of these bioactive peptides were using a specific bioassay method. It is likely that due to this reason the linear or more polar peptides are being missed during isolation. The most significant feature of sponge peptides is the presence of unusual amino acids, such as keto amino acids, and vinylogous amino acids in the molecules. Some peptides of blue-green algae and sponges share some common features in constituent amino acids. There remain some unanswered questions. For example, blue-green algae participate in the synthesis of peptides in sponges. Why are some peptides found in large quantities, while some are present in trace amounts? The answers to some of the questions may be arrived at when it will be possible to culture sponge cells or symbiotic microbes. Sponge peptides appear to have drug potential. Cyclotheonamides may serve as Lead compounds"for development of antithrombin drugs. Discodermins are potential antitumor promoting agents and calyculins are useful biochemical reagents.

3.3 Tunicates

There are roughly 2,000 living species of tunicates95-100 of which ascidians are the most abundant. Adult ascidians are sessile filter feeders, either solitary or colonial, and live preferentially in regions where there is freely flowing sea water. Tunicates (sea squirts) received relatively little attention from marine chemists. Over 50 secondary metabolites isolated so far from tunicates a number of them are peptides with significant biological activities. Peptides were first isolated in 1980 from Lissoclinum patella.101 The peptides of tunicates have been reviewed.16'102 Of the several peptides isolated from L. patella ulithiacyclamide103-07 (30) were found to be most active. It exhibited in vitro anticancer activity against L 1210 (0.1 |lg/mL), HeLa (0.1 |g/mL), and CEM (0.01 |lg/mL) cell lines103 and in vivo activity against the P 1534J murine leukaemia (TIC 188 at 1 mg/kg, repetitive doses). There are now 12 members of this cyclic peptides, all containing atleast one thiazole and usually an oxazoline amino acid. The oxazoline ring apparently plays an important role in the biological activity of ulithiacyclamide.

30

Trididemnum sp., a Caribbean tunicate, furnished didemnins A-C (32, 31, 33)108-117 a new class of cyclic depsipeptides. Didemnin-B had been synthesized.118 Didemnins exhibited impressive in vitro and in vivo antiviral activity.119 Didemnin-A and B inhibited Herpes simplex I and II at 1.0 ^M and 0.05 ^M concentrations, Rift Valley Fever virus at 1.37 and 0.04 ^g/mL, Venezuelan Equine encephalomyelitis at 0.43 and 0.08 ^g/mL, and yellow fever virus at 0.4 and 0.08 ^g/mL, respectively. Mice infected

Graphite Atomic Structure

xxX\NMeR

xxX\NMeR

with Rift Valley Fever virus showed 90% survival when treated with didemnin-B (31) at 0.25 mg/kg. There were, however, some drug related deaths at this dose.120 Didemin-B had in vivo anticancer activity against P 388 murine leukemia (TIC 199 at 1.0 mg/kg).119 It was subsequently evaluated in vitro against human tumors in a stem cell assay.121 Tumor cells from 8 of 17 patients showed sensitivity to didemnin-B with the median IC50 4.2 x 10-^g/mL. Didemnin-B (31) has completed phase II human clinical trials against advanced adenocarcinoma of the kidney,122 advanced epithelial ovarian cancer,123 and metastatic breast cancer.124 Unfortunately, it failed to show significant anticancer activity, but demonstrated significant toxicity. Didemnin-B had shown immuno-suppressant activity. In a Simonsen parental-to-F1 graft versus-hot assay, didemnin showed 71% inhibition of splenomegally with repetitive doses of 0.3 mg/kg.

3.4 Ascidians

Peptides continued to be one of the major classes of the secondary metabolites from ascidians. Several new didemnins have been reported since the structures of didemnin-A (32), B (31) and C (33) were determined.108,118 Several structures which were originally proposed on the basis of mass spectral data but were not confirmed. The structure of nordidemnin-B originally proposed on the basis of GC-MS analysis of hydrolysate products was confirmed by synthesis and NMR spectral data of the compound completely assigned.125,126 Didemnins Sand Y, which were new addition to the didemnin family of depsipeptides, contained three and four L-glutamine residues respectively, capped with a 3-hydroxydecanoyl unit as a new N-terminal blocking group. Conformational studies on didemnin-B and related analogs had been carried out.127-29 Biological activities of didemnins varied considerably on acy substitution pattern.130 For example, the cytotoxic activity was enhanced when the side chain was acetyl or longer. Acylating both the isostatin hydroxyl and the free N-methyl leucine amino group, or by bridging the amino groups of the N-methylleucine and the threonine moieties with methylene group, the cytotoxicity was reduced often without reduction of antiviral activity.130

The genus Lissoclinum is a rich source of cyclic peptides. Two classes of cyclic peptides, the heptapeptide lissoclinamides and the octapeptide patellamides, ulithiacyclamides have been isolated from the tunicate L. patella.131 Each of these classes of peptides have been characterized by the presence of thiazole and oxazoline amino acids. Recently, L. patella collected from different localities has furnished five new octapeptides

139134 135

lissoclinamides,132134 three new heptapeptides patellamides D and E and ulithiacyclamide (30).136 The amino acid sequence of all the lissoclinamides is the same. The difference lies in the oxidation states of the two sulphur containing rings and in the absolute stereochemistry of the amino acids. Most of the lissoclinamides exhibited only mild cytotoxicity. The exceptions are lissoclinamide which was cytotoxic against MRC54CVI and T24 cell lines with IC50 values of 0.04 ^g/mL and lissoclinamide which was found active against the same cell lines with an IC50 values of 0.8 ^g/mL. The other cyclic peptides isolated from collection of Lissoclinum patella were ulithiacyclamide-B and patellamides-D and E. Ulithiacyclamide-B incorporates a phenylalanine in place of the alanine found in ulithiacyclamide.137 The highly cytotoxic ulithiacyclamide B showed no selective activity against solid tumor cell lines. An X-ray analysis showed that patellamide-D adopts a severely folded conformation with the two thiazole rings nearly parallel to each other.29 This conformation which deviates drastically from the nearly square shape reported for the related peptide ascidiacyclamide,138 is stabilized by four transannular N-H-O hydrogen bonds.

Recently L. patella collected in the Southern Philippines had yielded two new cyclic octapeptides tawicyclamide-A and B.139 Tawicyclamides possess one thiazoline and two thiazole amino acids, but lacks oxazoline rings which were characteristic of all previously isolated Lissoclinum peptides. Twicyclamides and their dehydro analogs exhibited only weak cytotoxicity against human colon tumor cells (IC50 3 0 ^g/mL). L. patella collected in the Fiji islands has given a new class of cyclic peptides called patellins. The patellins include both hexapeptides and octapeptides, and are unique since they lack thiazole and oxazoline rings, instead contain a thiazoline ring and two novel threonine amino acids which are modified as their dimethylallyl ethers.140 Each peptide exits in solution as a mixture of conformers, complicating the interpretation of NMR spectral data. The structure determinations of patellins therefore, relied heavily on the evaluation of tandem mass spectral data.

Three new cyclic hexapeptides have been reported from the related ascidian Lissoclinum bistratum,14n44 collected from the Great Barrier Reef, Australia. Bistratamide-A contains oxazoline and thiazoline rings. Bistratamide-B also contains a second thiazole ring. Bistratamides A and B showed only marginal cytotoxicity against the human MRC5CVI fibroblasts and T 24 bladder carcinoma cells with IC50 in the range of 50 and 100 |g/mL respectively. The ascidian Cystodytes dellechiajei was the source of three cyclic peptides145 each of which was a symmetrical dimer of either L-Leu-L-Proc, L-Leu-L-Val, or L-Pro-L-Phe. The structure of these peptides had been determined by spectroscopic methods and confirmed by synthesis. These peptides were cytotoxic to L1210 leukemia with IC50 0.5 |g/mL. Diazonamides-A and B146149 are perhaps the most unusual peptides isolated from ascidians. They were isolated from Diazona chinensis collected in the Philippines. These chlorinated peptides are highly unsaturated, and derived from 3,4,5-tri-substituted L-tyrosine, tryptophan substituted at 2 and 4 positions of the indole moiety and L-valine. Diazonamide-A was cytotoxic in vitro against the human colon cancer HCT 116 and B 16 murine melanoma cell lines with IC50 values less than 15 ng/mL.

The majority of ascidian secondary metabolites have been isolated by extraction of whole body. However, some investigators have concentrated on specific tissues or physiological fluids. Two novel linear tetrapeptides, halocyamines A (34) and B (35), were isolated from the morula blood cells and from the blood of the solitary ascidian Halocynthia oretz.150,151 These peptides are composed of several amino acids which are unusual to ascidian secondary metabolites, including histidine-3,4-dihydroxyphenylalanine, and 6-bromo-8,9-didehydrotryptamine. The remaining amino acids of halocyamines-A (34) and B (35) were glycine and threonine, respectively.

Fisf Rna Cancer

Halocyamines exhibited antiviral activity against fish RNA viruses in RTG2 cells. They also showed antimicrobial activity against several Gram-positive bacteria and yeasts. Halocyamines were also cytotoxic to some cultured mammalian cells. Ascidian morula cells have been implicated in immunological responses such as phagocytosis and lysis of foreign substances. It is suggested that halocyamines which are found only in the morula cells of H. roretzi might be playing a role in the defense of this organism.

Ascidians remain unique among the marine invertebrates as they overwhelmingly produce nitrogen containing metabolites. Although investigations on ascidians as potential source of drugs were initiated more recently than on some other marine invertebrates, it is significant that the first marine natural product to enter human clinical trials, is didemnin-B (31), an ascidian secondary metabolite. A survey of the biological activities of the secondary asidian metabolites reveals that cytotoxicity is the most frequently observed activity against a variety of tumor cell lines. Next is antimicrobial activity followed by antiviral and antiinflammatory activities. These results however, are highly biased, reflecting the selection of assay system by individual researchers. A more reliable data on bioactivity would require new metabolites to be tested for a wider array of biomedically important activities. Ascidians, like many of the other marine invertebrates, are known to exist in obligate and non-obligate symbiosis with microorganisms. The unicellular prokaryotic alga Prochloron152'153 as well as other Cyanophytes154 are commonly associated with ascidians. The exact nature of the symbiosis is unclear, the increased incidence of algal-tunicate symbiosis in low nutrient tropical waters tends to suggest that the algae may play a nutritional role in the host's survival.155 The most interesting problem for natural product chemists is to know whether the symbionts contribute to the production of secondary metabolites. The isolation of biosynthetically unrelated secondary metabolites from a single ascidian organism may suggest different origins of each class of compounds. For example the lissoclinamides, patellamides and the patellazoles were obtained from Lissoclinum patella, an ascidian known to harbor Prochloron. Another example is that of Lissoclinum bistratum which was the source of the cyclic peptide bistratamides and the polyether bistratenes (bistramides). The findings of Hawakins et al141 reveal that bistratamides were localized in algal cells, while bistratenes were concentrated in tunicate tissue. These facts are consistent with different origins of these metabolites. The contribution of symbiotic alga to the biosynthesis of secondary metabolites of ascidian has not yet been elucidated because the symbiotic algae have been resistant to culture. However, there has been some success in the mariculture of ascidians. Evidence has been obtained that some secondary metabolites produced by ascidians provide a chemical defense.156 Didemnin-B (31), nordidemnin-B and patellamide-C have been demonstrated to have feeding deterrent activities towards generalist fishes in the field. Experimental results are beginning to supplant the long standing speculation about the ecological functions of marine secondary metabolites. However, much research remains to be done. Ascidians will undoubtedly, continue to be the source of novel secondary metabolites. However, the lack of a secure source of large quantities of material will make the development of these compounds difficult as pharmaceutical products. A potential solution to this problem involves the study and culture and symbiotic microorganisms.

3.5 Coelenterates

Soft corals, gorgonians, sea anemones, Portuguese man-of-war and jellyfish all come under coelenterates. Peptides most of which are venoms, have been isolated from these marine organisms. Coelenterate toxins can be divided into neuropeptides and neurotoxins. The first of these neuropeptides, a morphogenetic head activator, was isolated from a fresh water hydroid (Hydra attenuata). Subsequently, the sea anemone Anthopleura elegantissima was found to contain a substance which appeared identical by biological and chemical methods to the Hydra peptide. Twenty micrograms of the peptide was isolated from 200 kg of anemone and it was sequenced.157 Structurally, the peptide was unusual as it lacked a free amino terminus since the terminal glutamate was cyclized to a pyroglutamyl ring. This sequence was confirmed by synthesis. The head activator is required to initiate head specific growth and to affect the corresponding cellular differentiation.

The second groups of neuropeptides from coelenterates were related to the molluscan neuropeptide RMF amide. These peptides are believed to be ubiquitous in coelenterates. The largest groups of peptides from coelenterates are the neurotoxins from sea anemones. These neurotoxins could be divided into two groups, viz long and short. The long group of neurotoxins has 45-50 amino acids residues. These are further subdivided into type I and II. Type I was isolated from Anemonia sulcata158-60 and Anthopleura xanthogrammica.161,162 These peptides, show a great deal of sequence homology. All long toxins of type-II were isolated from anemones of the Stichodactylid family.161-66 These peptides also show a large degree of sequence homology. However, between the two types of long peptides, there is only a small amount of sequence homology, primarily in the N-terminal region. The second category of sea anemone neurotoxins is the "hort'peptides having about 30 amino acids residues. Despite the fact that there are three types of sea anemone toxins which share little sequence homology, all have the same mechanism of action. All alter the function of sodium channels in excitable membranes of muscles and nerves primarily by delaying the inactivation process. Because of this, the toxins are considered important probes of Na+ channels and related physiological functions. These peptides have been studied extensively for their physiological function and mechanism of action.167-172

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The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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